PROJECT SUMMARY/ABSTRACT Advanced age is the single most powerful risk factor for cardiovascular disease (CVD) for reasons that remain unclear. The contemporary paradigm of cardiovascular aging is that ventricular and vascular disease evolves over the life course in the setting of chronic exposure to traditional risk factors. However, the relative burden of CVD varies widely even among individuals of similar chronologic age and risk exposure. In effect, little is known about what causes the development and progression of subclinical CVD over an individual's lifetime. We postulate that discrete abnormalities in both myocardial and arterial function are among the earliest features of cardiovascular aging, developing in parallel and in response to cumulative risk factor exposure and, in turn, contributing to age-associated risk for CVD including heart failure (HF). In Aim 1, we will use advanced strain-based analyses of existing imaging data to assess variations in myocardial function in a large community-based sample of aging men and women in the Framingham Heart Study. We will also analyze the relation of these advanced myocardial measures with traditional risk factors, conventional echocardiographic traits, and pathway biomarkers associated with the development of HF. In Aim 2, we will examine the relations of these myocardial functional measures to incident HF, CVD, and mortality in the same aging sample. In Aim 3, we will use a novel methodology to prospectively assess arterial strain, a sensitive measure of arterial function, in a sample of adults free of baseline HF or CVD. We will examine the association of age-related variation in arterial strain to clinical correlates, concurrent myocardial function, and outcomes. The overarching goal of this proposal is to improve phenotyping of myocardial and arterial function - and determine the extent to which novel measures of pre-clinical dysfunction can clarify the pathway from risk factors to disease and also predict adverse outcomes. This research will be accomplished in the setting of a comprehensive career development program designed to provide the candidate with the skills needed to become an independent physician-scientist in cardiovascular medicine. An advisory committee of established scientists/mentors in the fields of epidemiology, cardiac and vascular imaging, aging biology, biostatistics, and translational science will guide the candidate in her transition to scientific independence over the course of the award period.